Cancers accumulate mutations that lead to neoantigens, novel peptides that elicit an immune response, and consequently undergo evolutionary selection. Here we establish how negative selection shapes the clonality of neoantigens in a growing cancer by constructing a mathematical model of neoantigen evolution. The model predicts that, without immune escape, tumor neoantigens are either clonal or at low frequency; hypermutated tumors can only establish after the evolution of immune escape. Moreover, the site frequency spectrum of somatic variants under negative selection appears more neutral as the strength of negative selection increases, which is consistent with classical neutral theory. These predictions are corroborated by the analysis of neoantigen frequencies and immune escape in exome and RNA sequencing data from 879 colon, stomach and endometrial cancers.

癌症积累突变，产生新抗原，即引发免疫反应的新型肽，并因此经历进化选择。在这里，我们通过构建新抗原进化的数学模型来确定负选择如何塑造生长中的癌症中新抗原的克隆性。该模型预测，如果没有免疫逃逸，肿瘤新抗原要么是克隆的，要么是低频率的；超突变肿瘤只有在免疫逃逸进化后才能形成。此外，随着负选择强度的增加，负选择下体细胞变异的位点频谱显得更加中性，这与经典中性理论是一致的。对 879 例结肠癌、胃癌和子宫内膜癌的外显子组和 RNA 测序数据的新抗原频率和免疫逃逸分析证实了这些预测。